Arthritis encompasses a group of conditions involving damage to the joints of the body. Arthritis is the leading cause of disability in people older than the age of fifty-five. The most common form of arthritis, osteoarthritis (OA) is a result of trauma to the joint, infection of the joint, or age. Osteoarthritis is a clinical syndrome in which low-grade inflammation results in pain in the joints, caused by abnormal wearing of the cartilage that covers and acts as a cushion inside joints and destruction or change of the characteristics of synovial fluid that lubricates those joints. As the bone surface becomes less well protected by cartilage, the patient experiences pain upon bearing weight, including walking and standing. Due to increased movement because of the pain, regional muscles may atrophy, and ligaments may become more lax.
Osteoarthritis affects nearly 21 million people in the United States, accounting for 25% of visits to primary care physicians, and half of non-steroidal anti-inflammatory drug (NSAID) prescriptions. It is estimated that 80% of the population will have radiographic evidence of osteoarthritis by age 65, although only 60% of those will be symptomatic.
Osteoarthritis is an increasingly common joint disease as the numbers of elderly people grow in many countries. In the US, for example, 10% of the population older than 60 years has OA. Current treatments for OA primarily involve the use of anti-inflammatory drugs, analgesics, and lubricating supplements. Therefore, it is a priority to develop agents that can suppress the progression of OA at an early-stage.
In patients with OA, chondrocytes are known to be able to resume phenotypic changes such as those occurring in epiphyseal growth plates, where chondrocytes undergo the process of terminal differentiation from hypertrophy to mineral deposition to eventual apoptosis (Blanco F J et al., Arthritis Rheum 1998; 41: 284-9; Kirsch T et al., Osteoarthritis Cartilage 2000; 8: 294-302). Chondrocytes in OA express the marker proteins of hypertrophic chondrocytes, including annexins, alkaline phosphatase, and type X collagen (Col X), but not type II collagen (Col II).
A feedback loop regulating endochondral ossification in growth plates involves parathyroid hormone-related peptide (PTHrP), Indian hedgehog (IHH), and Bcl-2. PTHrP maintains the function of proliferating chondrocytes and inhibits chondrocyte differentiation toward hypertrophy (Horton W E Jr et al., Matrix Biol 1998; 17: 107-15; Weisser J et al., Exp Cell Res, 2002; 279: 1-13). Previous reports have indicated that the biologic changes in articular chondrocytes during OA progression are similar to those of endochondral ossification (Blanco F J, et al., Arthritis Rheum 1998; 41: 284-9; Kirsch T et al., Osteoarthritis Cartilage 2000; 8: 294-302).
The biological changes of chondrocyte differentiation in growth plate are similar to that observed in the progression of osteoarthritis. It has been reported that in osteoarthritis, phenotypic changes for chondrocytes are similar to those in epiphyseal growth plates, wherein chondrocytes undergo terminal differentiation, hypertrophy, mineral deposition and eventually apoptosis (Arthritis. Rheum. (1998) 41(2): 284-9; Ann. Rheum. Dis. (2000) 59(12):959-65; Osteoarthritis Cartilage (2000) 8(4): 294-302). The chondrocytes in osteoarthritis express the marker proteins of hypertrophic chondrocytes, including annexins, alkaline phosphatase and type X collagen (Col X), but eliminate the expression of type II collagen (Col II).
It has been suggested that parathyroid hormone related protein (PTHrP) might be useful for the treatment of osteoarthritis. PCT patent application, WO2008/156725, for example, describes inhibition of articular cartilage mineralization by injecting PTHrP into the deep zone of articular cartilage. As noted above, chondrocyte differentiation involves complex processes, including cell proliferation, hypertrophy, terminal differentiation, mineralization and cell death (apoptosis). However, the art does not appear to provide any method that will reverse the degenerative process of chondrocytes, involving articular cartilage mineralization that occurs during development of osteoarthritis in a patient.
Accordingly, there is a need for methods that will inhibit or prevent cartilage mineralization and chondrocyte apoptosis, that will inhibit or reverse the degenerative process of chondrocytes in the early-stage of osteoarthritis, and that can be used for treatment of osteoarthritis, particularly early-stage osteoarthritis.